Bone Morphogenetic Protein (BMP)-9 ist ein Mediator von akuten und chronischen Antworten der Wundheilung der Leber und interagiert mit Transforming Growth Factor (TGF)-ß signalling

BMP-9 represents a relatively new member of the TGF-β superfamily of cytokines and although it is highly expressed in the liver its possible functions in liver cells are not well identified yet. This prompted us to investigate its expression and downstream signalling in primary mouse hepatocytes and hepatic stellate cells (HSC) in vitro as well as in acute and chronic CCl-4 mediated liver damage in vivo in mice. Within 3h after acute liver injury (single injection of CCl4 in mice) expression of BMP-9 and phosphorylation of its signal transducer, Smad-1, were strongly enhanced implying that BMP-9 participates in rapid wound-healing responses. Following BMP-9 induction we also detected increased expression of the direct BMP-9 target gene, Id1. Interestingly, phosphorylation of Smad-2, a signal transducer of the TGF-β pathway and transient upregulation of αSMA, a marker for HSC activation increased in parallel. BMP-9 and Id1 were also elevated after 4 weeks of chronic CCl4 administration, and neutralization of BMP-9 using a soluble, BMP-9 (and -10) specific receptor (AdALK1-Fc), reduced collagen deposition in the livers of these mice as measured by sirius red stainings. When analyzing the underlying molecular mechanism, we found that in the presence of TGF-β, BMP-9 dose-dependently induces apoptosis in primary mouse hepatocytes while increasing proliferation of HSC. Apoptosis induction in hepatocytes could be mimicked by adenoviral over-expression of Id-1. We further investigated BMP-9 effects on primary HSC and found that in the presence of a BMP/Smad-1 inhibitor (dorsomorphin), which does not inhibit TGF-β signalling, in vitro activation of the cells was completely blocked. Furthermore, BMP-9 reduced the TGF-β mediated EMT of hepatocytes in vitro.

These results imply that BMP-9 fine-tunes at least some TGF-β effects like apoptosis and EMT in hepatocytes and fibrogenic activation and proliferation of HSC. This results in a central role of BMP-9 during acute as well as chronic wound-healing responses of the liver. We thereby identified an important new regulator which modulates TGF-β effects in the liver in vitro and in vivo.

Organ- und Zellschädigung durch Alkohol: Mechanismen und Darstellung
Donnerstag, 20. September 2012/17:00–18:30/Saal A